Healthy Participants With Lower-than-average Mental Well-beingPhase 2SnSNCT06626139

Investigating the Interaction of Psilocybin and Context of Its Administration in Healthy Volunteers

A Phase 2 study testing Psilocybin, Context 1 and Context 2 in people with Healthy Participants With Lower-than-average Mental Well-being, run by Robin Carhart-Harris, PhD, MA at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

Who is it for?: Ages 21 to 70 yearsHealthy volunteers can take part
Conditions the study is for: Healthy Participants With Lower-than-average Mental Well-being
What is being tested?: Psilocybin, Context 1 and Context 2
Type of treatment: Lifestyle or therapy programme
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 120 participants
Where: 1 siteUnited States
Study dates: 20 Oct 2024to 30 Nov 2028
Phase: Phase 2
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 21 to 70 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

Participants will be considered for inclusion if they:
Are between 21 and 70 years of age
Are fluent in speaking and reading English
Are able to swallow pills/capsules
If able to become pregnant, must be non-lactating, have a negative pregnancy test at study entry and prior to each Experimental Session and must agree to an adequate form of birth control over the course of the study. Adequate forms of birth control include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal hormonal methods, abstinence, oral hormones plus a barrier contraception, vasectomized sole partner, or double barrier contraception. Two forms of contraception are required with any barrier method or oral hormones (i.e., condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom). Unable to become pregnant is defined as documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, and/or tubal ligation), permanently sterile by medical device such as Essure, postmenopausal, or assigned male sex at birth.
Able and willing to provide informed consent

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Able and willing to use computers and tablets or phones to enter electronic data
Agree to inform the investigators within 48 hours of any new or changed medical conditions.
Have an identified support person
For those dosed with psilocybin, their prior consent to be accompanied home (or to an otherwise safe destination) by a support person, chosen by them - ahead of time, or by a member of the study team.
Willing to provide contact details for a friend or family member, should there be an inability to make direct contact with the participant

Who cannot join

Participants will be excluded if they:
Have a current diagnosed psychiatric disorder that, in the opinion of the study clinician or PI, renders to person psychologically unstable or unduly vulnerable, or interferes with activities of daily living, or could impact attendance at or participation in study activities
Have a medically significant condition that renders the person unsuitable for the study
Give a positive alcohol breathalyzer test result on any study visit
A positive urine drug screen to any excluded substances prior to an Experimental Session, which warrants exclusion based on concerns that it may compromise safety or confound outcomes
Are breastfeeding, or have a positive pregnancy test at screening or at any point during the course of the study

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Systolic and diastolic BP values exceeding 139 SBP and exceeding 89 DBP and heart rate exceeding 90 bpm would result in exclusion from the study.
Present with a exceeding 450 msec or with evidence of cardiac damage, ischemia, or heart disease.
Have received an investigational drug within 30 days of the screening visit
Have an allergy or intolerance to any of the materials contained in either drug product or setting components, such as certain scents.
Have MRI contraindications (e.g., metal implants, pacemakers, claustrophobia etc.)
Have any current problem which, in the opinion of the investigator or clinician, might interfere with participation.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Hannes Kettner, MSc contact

4158495452

setandsetting@ucsf.edu

Avery Ostrand, MSc contact

avery.ostrand@ucsf.edu

United States1 site, 1 recruiting

UCSF Mission Bay
San Francisco, California, 94158
Kate Allison, BSc, setandsetting@ucsf.edu
Hannes Kettner, MSc, 4158495452, hannes.kettner@ucsf.edu
Recruiting

Other trials in United States

About this study

Official title: 2 x 2 Factorial, Double-blind, Randomized Trial of 'Set and Setting': a Translational Study in Healthy Volunteers

One hundred twenty healthy participants, ages 21 to 70, who experience moderate-to-lower-than-average mental well-being will be evenly randomized into four different study arms, using a 2x2 factorial design. Depending on the study arm, participants will either receive an inactive placebo or up to 25mg psilocybin (oral dose), in one of two set and setting conditions; drug administration contexts that are predicted to modulate drug effects.

The purpose of this study is to evaluate any interaction effects between an oral dose of psilocybin and the surrounding context (set and setting).

Read the detailed description

Recent research posits that psychedelic medicine is best employed as a combination treatment, i.e., as drug x psychological support or psychotherapy referred to for simplicity as 'psychedelic therapy'. It is assumed that positive outcomes via psychedelic therapy critically depend on a synergistic relationship between drug-induced brain and mind plasticity and supportive contextual factors (Carhart-Harris et al., 2018; Carhart-Harris and Friston, 2019). These contextual factors have been referred to as 'set and setting' (Leary et al., 1963) or 'extrapharmacological'- highlighting elements beyond the drug that contribute to relevant outcomes (Hartogsohn, 2016).

The proposed experiment is a double-blind, randomized between-subjects 2 x 2 factorial study in 120 volunteers who experience low psychological well-being at baseline and have limited prior experience with psychedelics (1:1:1:1, n = 30 per condition). The main aim of the study is to assess the contribution of a select number of pre-defined contextual variables (both 'set' and 'setting') on the nature and trajectory of effects linked to a single dosing session with either psilocybin (oral, 25mg) or placebo (oral, inert).

The study will have four primary outcomes, two pertaining to mental health, namely: changes in psychological well-being - as measured via the Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS), from baseline to 4 weeks post dosing session (primary endpoint) and changes in the Watts Connectedness Scale (WCS) at consistent timepoints. The two primary outcomes indexing the quality of the acute experience will be: Emotional Breakthrough - measured via mean scores on the Emotional Breakthrough Inventory (EBI), and Challenging experience (CE) - defined and measured here as scores on the following four sub-factors of the Challenging Experience Questionnaire (CEQ): fear, insanity, isolation, and paranoia.

Conditions: Healthy Participants With Lower-than-average Mental Well-being
Being tested: Psilocybin, Context 1, Context 2, Placebo
Keywords: well-being, psilocybin, psychedelic, neuroimaging, healthy volunteers

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PsilocybinDrug
Healthy participants will receive up to 25 mg psilocybin.
Context 1Behavioural
Drug administration will take place in a context (Context 1) that is expected to modulate acute and post-acute drug effects.
Context 2Behavioural
Drug administration will take place in a context (Context 2) that is expected to modulate acute and post-acute drug effects.
PlaceboDrug
Healthy participants will receive an inactive placebo.

Study groups in NCT06626139
Study group	Role	What they receive
Psilocybin C1	Experimental	Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects. Receives: Drug: Psilocybin; Behavioral: Context 1
Psilocybin C2	Experimental	Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects. Receives: Drug: Psilocybin; Behavioral: Context 2
Placebo C1	Placebo comparator	Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects. Receives: Behavioral: Context 1; Drug: Placebo
Placebo C2	Placebo comparator	Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects. Receives: Behavioral: Context 2; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Challenging Experience Questionnaire (CEQ) subscales score
The Challenging Experience Questionnaire is designed to measure challenging psychological experiences associated with the acute effects of psilocybin. For this study, the combined score across four our of its seven subscales will be used as a primary outcome: Fear, Insanity, Isolation, and Paranoia, excluding Grief, Physical Distress, and Death subscales. Scaled scores range from 0 to 100. Higher scores indicate higher levels of challenging experience (worse outcome).
Measured: Eight hours post-dose.
Change in Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score from Baseline to 28 days post-dose
The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) was developed to enable the monitoring of mental wellbeing in the general population and the evaluation of projects, programmes and policies which aim to improve mental wellbeing. Scores range form 14 to 70. Higher scores indicate higher levels of mental well-being (better outcome).
Measured: Baseline to 28 days post-dose.
Change in Watts Connectedness Scale (WCS) scores from Baseline to 28 days post-dose
The WCS is a 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. Scores range from 0 to 100. Higher scores indicate higher levels of connectedness (better outcome).
Measured: Baseline to 28 days post-dose.
Emotional Breakthrough Inventory (EBI) score
The Emotional Breakthrough Inventory was developed to assess emotional breakthrough, an important and distinct component of the acute psychedelic experience. Scores range from 0 to 100. Higher scores indicate higher levels of emotional breakthrough (better outcome).
Measured: Eight hours post-dose.

Secondary outcomes (9)

Changes in resting state BOLD activity viafunctional magnetic resonance imaging (fMRI)
Assessment parameters include: Eyes-closed resting state fMRI
Measured: Baseline to 28 days post-dose.
Changes in BOLD activity during emotional processing via functional magnetic resonance imaging (fMRI)
Assessment parameters include: BOLD response during an emotional processing task
Measured: Baseline to 28 days post-dose.
Changes in white matter organization via magnetic resonance imaging (MRI)
Assessment parameters include: Diffusion Tensor Imaging (DTI)
Measured: Baseline to 28 days post-dose.
Structural brain changes via magnetic resonance imaging (MRI)
Assessment parameters include: T1- and T2-weighted imaging
Measured: Baseline to 28 days post-dose.
Acute Lempel Ziv Complexity (LZC) via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Lempel Ziv Complexity (LZC)
Measured: Pre-dose; 2, 4, and 6 hours post-dose
Spectral power in traditional frequency bands via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Spectral power in traditional frequency bands
Measured: Pre-dose; 2, 4, and 6 hours post-dose
Transfer entropy and integrated information via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Transfer entropy and integrated information
Measured: Pre-dose; 2, 4, and 6 hours post-dose
Synergistic and redundant activity patterns via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Analytic approaches include: Partial information decomposition
Measured: Pre-dose; 2, 4, and 6 hours post-dose
Travelling waves via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include:
Travelling waves
Measured: Pre-dose; 2, 4, and 6 hours post-dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

20 Oct 202430 Nov 2028

First posted3 Oct 2024
Study start20 Oct 2024
Primary completion30 Nov 2027 (estimated)
Study completion30 Nov 2028 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Healthy Participants With Lower-than-average Mental Well-beingStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Basic science
Allocation: Randomised
Intervention model: Factorial
Model description: 2 x 2 Factorial Design Factor 1: Drug (Psilocybin vs Placebo) Factor 2: Context (Context 1 vs Context 2)
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 120 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT06626139
Sponsor's protocol ID: 23-38706
Acronym: SnS
Status last verified: Jun 2026
First submitted: 27 Sep 2024
Last updated: 4 Jun 2026
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Study at a glance

From the registry record, last updated by the sponsor on 4 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 2 x 2 Factorial, Double-blind, Randomized Trial of 'Set and Setting': a Translational Study in Healthy Volunteers
ClinicalTrials.gov ID: NCT06626139
Acronym / sponsor ID: SnS / 23-38706
Conditions: Healthy Participants With Lower-than-average Mental Well-being
Keywords: well-being, psilocybin, psychedelic, neuroimaging, healthy volunteers
Phase: Phase 2
Study type: Interventional
Recruitment status: Recruiting
Enrolment: 120 participants (estimated)
Lead sponsor: Robin Carhart-Harris, PhD, MAUniversity, hospital or other
Study start: 20 Oct 2024 (actual)
Primary completion: 30 Nov 2027 (estimated)
Study completion: 30 Nov 2028 (estimated)
First posted: 3 Oct 2024 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The purpose of this study is to evaluate any interaction effects between an oral dose of psilocybin and the surrounding context (set and setting).

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Factorial
Masking: Double blind (participant, investigator)
Number of arms: 4
Model description: 2 x 2 Factorial Design Factor 1: Drug (Psilocybin vs Placebo) Factor 2: Context (Context 1 vs Context 2)

Arm	Type	Receives
Psilocybin C1	Experimental	Drug: Psilocybin, Behavioral: Context 1Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Psilocybin C2	Experimental	Drug: Psilocybin, Behavioral: Context 2Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.
Placebo C1	Placebo comparator	Behavioral: Context 1, Drug: PlaceboFollowing screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Placebo C2	Placebo comparator	Behavioral: Context 2, Drug: PlaceboFollowing screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.

Who may qualify

Ages: 21 to 70 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (11 listed)

Are between 21 and 70 years of age
Are fluent in speaking and reading English
Are able to swallow pills/capsules
If able to become pregnant, must be non-lactating, have a negative pregnancy test at study entry and prior to each Experimental Session and must agree to an adequate form of birth control over the course of the study. Adequate forms of birth control include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal hormonal methods, abstinence, oral hormones plus a barrier contraception, vasectomized sole partner, or double barrier contraception. Two forms of contraception are required with any barrier method or oral hormones (i.e., condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom). Unable to become pregnant is defined as documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, and/or tubal ligation), permanently sterile by medical device such as Essure, postmenopausal, or assigned male sex at birth.
Able and willing to provide informed consent

Key exclusion criteria (12 listed)

Have a current diagnosed psychiatric disorder that, in the opinion of the study clinician or PI, renders to person psychologically unstable or unduly vulnerable, or interferes with activities of daily living, or could impact attendance at or participation in study activities
Have a medically significant condition that renders the person unsuitable for the study
Give a positive alcohol breathalyzer test result on any study visit
A positive urine drug screen to any excluded substances prior to an Experimental Session, which warrants exclusion based on concerns that it may compromise safety or confound outcomes
Are breastfeeding, or have a positive pregnancy test at screening or at any point during the course of the study

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
PsilocybinHealthy participants will receive up to 25 mg psilocybin.	Drug	Psilocybin C1, Psilocybin C2
Context 1Drug administration will take place in a context (Context 1) that is expected to modulate acute and post-acute drug effects.	Behavioural	Placebo C1, Psilocybin C1
Context 2Drug administration will take place in a context (Context 2) that is expected to modulate acute and post-acute drug effects.	Behavioural	Placebo C2, Psilocybin C2
PlaceboHealthy participants will receive an inactive placebo.	Drug	Placebo C1, Placebo C2

Primary outcome

Challenging Experience Questionnaire (CEQ) subscales score
Time frame: Eight hours post-dose.
The Challenging Experience Questionnaire is designed to measure challenging psychological experiences associated with the acute effects of psilocybin. For this study, the combined score across four our of its seven subscales will be used as a primary outcome: Fear, Insanity, Isolation, and Paranoia, excluding Grief, Physical Distress, and Death subscales. Scaled scores range from 0 to 100. Higher scores indicate higher levels of challenging experience (worse outcome).
Change in Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score from Baseline to 28 days post-dose
Time frame: Baseline to 28 days post-dose.
The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) was developed to enable the monitoring of mental wellbeing in the general population and the evaluation of projects, programmes and policies which aim to improve mental wellbeing. Scores range form 14 to 70. Higher scores indicate higher levels of mental well-being (better outcome).
Change in Watts Connectedness Scale (WCS) scores from Baseline to 28 days post-dose
Time frame: Baseline to 28 days post-dose.
The WCS is a 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. Scores range from 0 to 100. Higher scores indicate higher levels of connectedness (better outcome).
Emotional Breakthrough Inventory (EBI) score
Time frame: Eight hours post-dose.
The Emotional Breakthrough Inventory was developed to assess emotional breakthrough, an important and distinct component of the acute psychedelic experience. Scores range from 0 to 100. Higher scores indicate higher levels of emotional breakthrough (better outcome).

9 secondary outcomes

Changes in resting state BOLD activity viafunctional magnetic resonance imaging (fMRI)
Time frame: Baseline to 28 days post-dose.
Changes in BOLD activity during emotional processing via functional magnetic resonance imaging (fMRI)
Time frame: Baseline to 28 days post-dose.
Changes in white matter organization via magnetic resonance imaging (MRI)
Time frame: Baseline to 28 days post-dose.
Structural brain changes via magnetic resonance imaging (MRI)
Time frame: Baseline to 28 days post-dose.
Acute Lempel Ziv Complexity (LZC) via Electroencephalography (EEG)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Spectral power in traditional frequency bands via Electroencephalography (EEG)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Transfer entropy and integrated information via Electroencephalography (EEG)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Synergistic and redundant activity patterns via Electroencephalography (EEG)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Travelling waves via Electroencephalography (EEG)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2026.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.

Hannes Kettner, MSc contact

4158495452

setandsetting@ucsf.edu

Avery Ostrand, MSc contact

avery.ostrand@ucsf.edu

Robin Carhart-Harris, PhD principal investigator

University of California, San Francisco

Jennifer Mitchell, PhD principal investigator

University of California, San Francisco

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Hannes Kettner, MSc (4158495452, setandsetting@ucsf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Challenging Experience Questionnaire (CEQ) subscales score (time frame: Eight hours post-dose.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06626139.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2026.